Project Summary/Abstract: DESCRIPTION: Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic islet ?-cells ? a long asymptomatic period spanning many months to years. Currently, autoantibodies to ? cell autoantigens serve to identify those at increased risk, yet additional biomarkers are needed to better understand the ?-cell destruction process and predict progression from persistent islet autoimmunity (IA) to T1D. We hypothesize that: 1) protein profiles in serial blood plasma samples collected prior to and after development of islet autoantibodies will predict time to T1D onset independently of islet autoantibodies; and 2) proteins released from the pancreas into the peripheral blood contain signatures of the ongoing ?-cell destruction process during the pre-T1D phase. The long-term goal of this project is to provide better diagnostic and prognostic markers so IA positive subjects can be staged for individualized therapy to prevent overt T1D, and to gain additional insights into the pathogenesis of this disease. In the present application, we are aiming to identify pancreatic and ?-cell specific protein markers in plasma that are associated with the appearance of IA and predict the rate of progression from IA to T1D. This will be achieved using advanced proteomic technologies and by comparative analysis of longitudinal plasma proteome profiles of subjects with T1D, pre- diabetic IA and controls enrolled in large scale longitudinal clinical studies.